TW201127375A - Taste masked topiramate composition and an orally disintegrating tablet comprising the same - Google Patents

Abstract

In various embodiments, the present invention is directed to a taste masked pharmaceutical composition comprising a therapeutically effective amount of taste masked sulfamate-substituted monosaccharide particles comprising a sulfamate-substituted monosaccharide or a pharmaceutically acceptable salt or derivative thereof that are coated with one or more taste-masking layers, and optionally one or more of taste-masked neltrexone, 5-HT3 receptor antagonist, phentermine, and vitamin B-12. The present invention relates to methods of making the taste masked and ODT compositions, and methods of using the compositions for treating a patient subject to an epileptic condition, migraines, dysphagia, achieving / maintaining weight loss, or alcoholism or drug addiction.

Description

201127375 VI. INSTRUCTIONS: CROSS-REFERENCE TO RELATED APPLICATIONS This application is hereby filed in 2011. The U.S. Provisional Application No. 6 1/293,45 5, filed on March 8th, is hereby incorporated by reference in its entirety for all its purposes. [Prior Art] Because of fear of gas. Furthermore, difficulty swallowing or difficulty in the downtime is common in all age groups. For example, it was observed that in about 35% of the general population, and another 30%-40% of middle-aged patients who were sent to specialized agencies and among all 8%-22% of long-term care institutions (Many of them need regular medications to refrain from the quality of their lives.) They may have difficulty swallowing. This may result in poor compliance or even non-compliance with the treatment of oral music and is therefore audible. This has a negative effect on the efficacy of such treatments in monotherapy or adjuvant therapy. r For a group of patients with epilepsy, the target of treatment is to maintain a sufficient painful episode of the subject. At both levels and to prevent compliance with additional drug regimens for two pairs of prescription drugs in the blood. , maintain > alpha therapeutic material 6 scoop concentration is necessary for topiramate, 2,3:4,5 · double · 〇 _ different convex & w bingya two base - β-D-pyranium real estate * * salt Has the following structural formula (1). Fructose cyano%

I53421.doc 201127375 Topiramate is the active ingredient in T0PAMAX®, a commercially available product, TOPAMAX® is used as an anti-epileptic drug, beta topiramate, as a pre-existing or primary systemic tonic-clonic epileptic seizure. An initial monotherapy in patients aged 10 years and older. Topiramate tablets or capsules are also indicated for use in adults with partial episodes of epileptic seizures, or primary systemic tonic-clonic seizures, as well as pediatric patients aged 2-16 years, and with Lenn〇 Adjuvant therapy in patients aged 2 years and older in seizures associated with x_Gastaut syndrome. The purpose of the care was also pointed out for adults to prevent migraine. TOPAMAX® tablets can be obtained in the form of 25 mg, 5 bark, 1 bark, and 200 mg round tablets for oral administration, or TOMAPM capsules can be 5 mg and barked Obtained in the form of a dispersible capsule for oral administration, the dispersion capsule is orally administered as a whole capsule or by opening it and m to a soft food. However, care. There is a bitter taste than the §. ODT formulations should be sigma, for example they should have acceptable, official characteristics (such as good taste and mouthfeel) to maintain patient compliance or adherence to the music program 'because 0DT tablets are designed to be in patients The σ cavity causes disintegration. ODT compositions should also exhibit acceptable pharmacokinetic and bioavailability characteristics to provide a desired therapeutic effect comparable to non-qdt dosage forms (eg, conventional tablets, capsules, etc.), thereby avoiding relative Expensive in vivo efficacy testing and validation of such conventional dosage forms. For a bitter (four), a clear formulation usually requires a taste masking layer to be applied to the particles containing the music to improve the sensation properties of the 0DT formulation, so that the taste and taste of the ODT of the solution is 153421.doc 201127375 Until the contents of the dosage form are swallowed (typically without water or other fluids), it is still acceptable to the subject. However, taste masking may inhibit or delay drug release, thereby providing unacceptable pharmacokinetic properties. Conversely, certain components of the formulation may promote rapid release and, therefore, may result in undesirable taste or mouthfeel characteristics. According to local regulations, such as "Guideline f〇r Bi〇e is called 丨aw

Studies^ Generic Pr〇ducts (required by Japanese government regulations), in general, a pharmaceutical product is also required to meet not only certain bioequivalence indicators, but also certain dissolution requirements. For example, if the dissolution rate of a test product and a reference product shows "a specific significant difference in a dissolution medium for an alkaline drug at Ρΐί=6·8 or PH between 3·〇 and 6.8," An expensive, time consuming, and/or "non-raised" bioequivalence study may be required in a subject with low gastric acidity. Significant differences can mean or (1) at the time point when the average dissolution rate of the product with higher dissolution reaches 8〇%, the average dissolution rate of other products does not reach 5G%; or (7)# at the specified test time = The average dissolution rate of the two products is not ❹m%J1 and the average dissolution rate of other products with slower dissolution at the end of the specified test time does not reach 60% of the average dissolution rate of the other products. Thus, an acceptable ODT formulation should balance these contradictory features to provide a palatable (e.g., taste masking) with acceptable in vitro and/or in vivo dissolution profiles and acceptable pharmacokinetics. Fast 153421.doc 201127375 Fast disintegrating composition. Although there are no 〇DT formulations including topiramate microparticles that meet the following specifications: σ · 〇〇· > topiramate-containing microparticles, which are not only effectively masked but also exhibit a regulatory requirement Dissolution curve; > ODT includes rapidly dispersing pellets to rapidly disintegrate upon contact with saliva in the mouth to form a smooth, easy-to-swallow suspension containing a taste-masked microparticle comprising a beta-beta ester; > particles containing enthalpy than vinegar have an average particle size of no more than 4 μηηι to provide a smooth mouthfeel before being swallowed without leaving a aftertaste (ie, little or minimal without grit or whiteness) Drug Release); > Provides a rapid, substantially complete release of topiramate when it reaches the stomach to be bioequivalent to a reference list drug (RLD) (ie, immediate release of the reference list drug product, ΤΟΡΑΜΑΧ®). > ODT formulations exhibit acceptable tablet hardness and brittleness for use in packaging into high density polyethylene (HDPE) bottles or blister for transportation and commercial distribution. SUMMARY OF THE INVENTION The present invention relates to a taste masking pharmaceutical composition. In particular, the present disclosure relates to a taste masked pharmaceutical composition comprising a therapeutically effective amount of taste-masked sulfamate-substituted monosaccharide particles comprising a sulfamate-substituted monosaccharide or a pharmaceutically acceptable salt or derivative thereof, and wherein the microparticles are coated with one or more taste masking layers to mask the taste of the aminoglycolate substituted monosaccharide; wherein the taste masking Layer includes at least one

S 153421.doc 201127375 A water-insoluble polymer. The disclosure also relates to an immediate release (ir) orally disintegrating tablet (coffee)! The orally disintegrating tablet comprises a therapeutically effective amount of a collection of particles, wherein each particle comprises (1) microparticles coated with one or more taste masking layers, the microparticles comprising a torbic ratio or an amino stone a salt of a xanthate-substituted monosaccharide or a pharmaceutically acceptable salt thereof, and (1) a rapidly divided microparticulate agent comprising at least one disintegrant and at least one sugar alcohol and/or at least A saccharide; wherein the taste layer/taste mask layer comprises - a water-insoluble polymer. The present disclosure also relates to methods of making the taste masking and sputum compositions, and the use of the compositions of the present invention for treating a patient suffering from an epileptogenic disorder, complication or migraine, and/or for achieving / Maintaining weight loss, and/or treating or treating alcoholism and/or drug formation methods. In an embodiment, the invention is directed to a taste masked pharmaceutical composition comprising a therapeutically effective amount of a taste-masked amino acid salt-substituted monosaccharide particle comprising an amino acid salt substituted a monosaccharide or a pharmaceutically acceptable salt or derivative thereof, wherein the particles are coated with one or more taste masking layers to mask the taste of the monosaccharide substituted by the amino acid hydrochloride. The scent layer includes at least one type of water-insoluble polymer. In another embodiment, the invention is directed to a __ orally disintegrating tablet (10), the disintegrating tablet comprising a therapeutically effective amount of a collection of particles, wherein each particle comprises a microparticle "the microparticle" Included in a sputum vinegar, an amino sulphate substituted monosaccharide or a pharmaceutically acceptable salt or derivative thereof (wherein the microparticles are coated with a taste masking layer), a rapidly dispersing microgranule ( The microgranule comprises at least one disintegrant and at least two sugar alcohols and/or at least two 153421.doc 201127375 sugars; and wherein the taste masking layer comprises a water insoluble polymer. In yet another embodiment, the invention relates to various methods of making the taste masking and ODT compositions. In another embodiment, the invention relates to a method of using a composition of the invention for treating a patient suffering from an epileptic disorder, treating a patient to induce or maintain weight loss, or treating a patient suffering from migraine. These and other embodiments will be described in detail below. DETAILED DESCRIPTION OF THE INVENTION The following description includes information that may be useful in understanding the present invention. As used above, and throughout the specification of the present invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings: As used herein, the terms "drug", "active", "active ingredient" or "active" The pharmaceutical ingredient includes any pharmaceutically acceptable and therapeutically effective compound, pharmaceutically acceptable salt, stereoisomer, and mixture of stereoisomers, solvates (including hydrates), and/or derivatives thereof. A suitable pharmaceutical system is topiramate according to the invention. Further, the terms "derivative", "various derivatives" or "various derivatives thereof" as used herein include various compounds related to vinegar. For example, in certain embodiments, a toribidine- and/or a sulfamate-substituted π-saccharide derivative may include a compound of the formula: Early. X, R1 R, 1

153421.doc 201127375 wherein each instance of R, is independently selected from the group consisting of hydrazine, hydroxy, cyano, nitdto, F, Cl, Br, I, trifluoromethyl,曱% acid salt, benzene sulfonate, (Ci_C6) alkyl group, hydroxy (C _C6) alkyl group, (G-C6) alkane fluorenyl group, aryl (Ci_C6) alkyl group. In certain embodiments, the term "salt" or "methyl" refers to a product formed by the reaction of a suitable inorganic or organic acid with the "free domain" form of the drug. Suitable acids include those which have sufficient acidity to form a stable salt, such as an acid having low inertness, such as salts approved for use in humans or animals. Non-limiting examples of various acids that can be used to form the salt of topiramate include inorganic acids such as HF, HCn, HBr, HI, Mail 4, Time 4; non-limiting examples of organic acids include organic sulfonic acids such as C^6 Arylsulfonic acid, C6_10 heteroarylsulfonic acid or Cl·! 6 alkylsulfonic acid - such as phenyl, α-naphthyl, β-naphthyl, (s)-camphor, fluorenyl, ethyl, n-propyl , isopropyl, n-butyl, secondary butyl, isobutyl, secondary butyl, pentyl and hexyl carboxylic acid; non-limiting examples of organic acids include carboxylic acids such as C 丨 丨 6 alkyl, c0 _丨6 aryl carboxylic acid and (: 4-16 heteroaryl acid, such as acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, glutaric acid, tartaric acid, citric acid, fumaric acid, succinic acid, malic acid , maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, and 2-phenoxybenzoic acid; non-limiting examples of organic acids include amino acids, such as naturally occurring Amino acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc. His suitable salt can be found, for example, in s. M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19. (For all purposes 153421.doc -10- 201127375 In the present invention, "salt" refers to a salt that is biocompatible or pharmaceutically acceptable or particularly non-toxic to mammalian cells. The salt of the drug useful in the present invention may be crystalline. a mixture of amorphous or different crystalline forms and/or a mixture of crystalline forms and amorphous forms. The term "prodrug" means a form of a compound of the formula and/or 13 [, which is of the formula 1 and/or 11 Suitable for administration to patients without excessive toxicity! • irritating, allergic reactions, etc., and effective for their intended use, including ketals, esters, and zwitterions. For example, by hydrolysis in the blood, A prodrug is converted in vivo to produce a compound of formula 1 and 7 or formula 11. A thorough discussion is provided in T.

Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V〇l. H of the A. C. S. Symposium Series and at £3^^(16·

Roche, ed., Bioreversible Carriers in Drug Design, • Can Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. The term "orally disintegrating tablet", "oral dispersible tablet", or "ODT" refers to a solid dosage form of the present invention which does not require chewing to rapidly disintegrate in the oral cavity of a patient after administration. When tested as described herein (eg, USP 701 >/), the rate of disintegration can vary, but is a conventional solid dosage form (eg, tablets, capsules) that is intended to be swallowed immediately after administration. , etc.) has a faster rate of disintegration or a faster disintegration rate than a chewable solid dosage form. The ODT compositions of the present invention may comprise pharmaceutically acceptable ingredients which swell, dissolve or otherwise contribute to the disintegration or dissolution of the ODT composition 153421.doc 201127375. The term "unit dose" refers to a pharmaceutical composition comprising an amount of a drug intended to be administered to a patient in a single dose. The term "about" as used herein refers to a quantity, including the quantity indicated and the value close to the quantity. For example, "about 60 seconds" includes values that are exactly 6 seconds and close to 60 seconds (eg, 50 seconds, 55 seconds, 5 9 seconds, 61 seconds, 65 seconds, 70 seconds, etc.). In some cases, the term "about [a value]" can be understood to mean within a certain percentage of the value. Thus, "about 100" can include a range of up to i 5% in the vicinity of a value i00 (eg, from 85 to 11 5, endpoints are included), and similarly, the term can be included in the vicinity of a value. Up to 4%, 13.3%, 12%, 11%, 1 〇〇/. , 9%, 8%, 7°/〇, 6%, 5%, 4. /〇, 3. A range of /〇, 2%, 1%, or less than 1%. Regarding the 〇DT tablet composition of the present invention, the term "substantially disintegrating" indicates that the ODT tablet largely disintegrates into its constituent particles or microparticles which have been previously compressed into tablets. About 50%, at least about 60%, to >, and force 70/. At least about, at least about, or about 〇dt tablets have disintegrated into their constituent granules. Similarly, the term "substantially soluble" with respect to the ODT sheet of the present invention means that the percentage of the active pharmaceutical ingredient released or ** from the tablet is present in the group. In the matter. At least about 50%, at least about 60%, at least about 70%, at least about 8λ〇/, U/. At least about 90%, or about 1%. Although the characteristics or characteristics of these product components are described, terms such as "containing a carrier or a percentage of "~ ^ only topiramate-free particles released" are used; 153421.doc •12 · 201127375 However, the terms are equally applicable to other components of the group comprising the amino sugar salt. The terms "particles", "microparticles", early and "microgranules" are used interchangeably herein to mean 糂屮β丄? One particle of the granules having a mean particle size of not more than 400 μηι is not considered; and in some embodiments, it does not exceed 300 _. The term "= there is a drug-containing if:---masking taste that does not exceed the average particle size" means an undesired taste that masks a drug (a process that is included) by using a sufficiently thick barrier The layer is achieved by the particles of each piece of music. Unless otherwise indicated, all percentages and ratios are calculated by weight. Unless otherwise indicated, all percentages are calculated based on the total composition. The microparticles are described as primary particles or primary particles. The primary particles are primary particles that are not agglomerated and the secondary particles are agglomerated. Thus, in general, the primary particles are smaller than the secondary particles. For an orally disintegrating tablet (〇dt) combination 2, the composition comprises a therapeutically effective amount of a collection of particles (where each particle comprises a coating with a taste masking layer) and a rapidly dispersing microgranule. Another mode of application of this month is directed to a collection of particles, each of which is a drug-layered bead comprising an inert core coated with a layer containing torazole. In the embodiment, the taste masking layer comprises a water-insoluble taste-masking poly- or a water-insoluble taste-masking polymer combined with a water-soluble or stomach-soluble polymer. 153421.doc -13· The method of the 201127375 compound is directed to the preparation of the coffee cake masking μ 2 of the present invention. The method comprises preparing microparticles comprising the carrier (IV); using a microparticle of (tetra) and two "tetra"; the preparation comprises - disintegration a granule combined with a saccharide of the right glutinous rice cultivar (referred to as a rapidly dispersing granule === a granule of a decomposing agent); the smear containing the smear layer and containing disintegration The pellets of the agent, and optionally other pharmaceutically acceptable knives, are mixed; and the mixture is compressed into (10) L of the composition. In yet another embodiment, the invention is directed to a treatment for epilepsy ( A method of early-therapy or adjuvant therapy, a patient suffering from migraine, and/or treating a patient to induce or maintain weight loss, the method comprising administering an ODT composition of the invention. The topiramate-containing particles may comprise crystalline topiramate, and One or more pharmaceutically acceptable forms (eg, fillers, binders, etc.) granulated topiramate, inert core layered beads having a topiramate-containing pellet (for example, prepared by coating in a fluid bed coater) or Beads containing a layer of inert core than vinegar pellets (for example, prepared by vect〇r, s Granurex by controlled spheronization or powder layering) ^ for example, 'crystallized trays. a primary particle having an average particle size ranging from about 1 cm to 300 μm, including about 丨5 〇μπι, about 丨-丨 (10) μπι, about 1-150 μηη, about 1-200 μηι, about 1-250 μηη, about 50-100 μηη, about 50-150 μηι, about 50-200 μηι, about 50-250 μηι, about 50-300 μηη, about 100-150 μηη, about 100.200 μπχ, about 150-200 μηη, about 150-250 μη , about 150-300 μπι, about 200-250 μηι, about 200-300 μπι, or about 250-300 μηι 〇153421.doc •14- 201127375 When containing pellet pellets or drug G_rex pellets Trust. The particles of the vinegar include at least one binder of the J film. The binder may be included to form the contained carrier. Any suitable binder for the cups of the particles of the ester. Non-limiting examples of suitable film forming primers may include water soluble, alcohol soluble or acetone/water soluble binders such as polyvinylpyrrolidone (pvp), corn starch, polyethylene oxide , #乙: alcohol, M propyl methylcellulose (10) batch, methyl cellulose, propyl propyl cellulose (Hpc). The amount of the binder forming the film in the particles containing the core can be from about 5% to about 5%. , including approximately 5.5/0-1/〇, approximately 5%_2%, approximately 5% 5%, approximately 5%·7%, approximately 1%-2%, approximately 1%_5%, approximately 1 % 7%, about 1% 〇%, about, about 2%-7%, about 2%-1%%, about 5%-7%, about 5%_1%%, and about 10%. The topiramate-containing particles described herein may also include other pharmaceutically acceptable ingredients such as fillers, diluents or other excipients. Non-limiting examples of other pharmaceutically acceptable ingredients for the drug-containing pellets include, for example, mannitol, lactose, microcrystalline cellulose, potassium sulfate, calcium silicate, modified starch, and mixtures thereof. The amount of other pharmaceutically acceptable ingredients (e.g., fillers, diluents, or other excipients) in the topiramate-containing granules can range from about 5°/. -80%, including about 5%-70%, about 50/〇_60%, about 5%-50%, about 5%-40%, about 5%-30%, about 5%-20. /〇, about 5%-15%, about 5%-10%, about 1%-70%, about 100/〇-60%, about 10%-50%, about 10〇/〇-40%, about 1〇%-3〇%, about 1〇%-20%, about 10%-15%, about 20%-70%, about 20%-60%, about 20%-5 0%, about 153421.doc - 15- 201127375 20%-40°/〇, about 20%-30%, about 20%_25%, about 30%-70%, about 30%-60%, about 30%-50%, about 30%-40 %, about 30% - 35%, about 40% - 70% 'about 40% - 60%, about 40% - 50%, about 40% - 45. /〇, about 50%-70%, about 50%-60%, about 50%-55%, about 60%-70%, or about 60%-65〇/〇. In another embodiment, the drug-containing core described herein can be in a tray. The form of Granurex pellets layered into lamellae beads or layers comprising a core powder', e.g., with a toluene comprising a topiramate and a polymeric binder. A pharmaceutically acceptable sugar sphere or cellulose sphere coated with a layer other than the S (eg, 'Celphere® from Asahi Kasei or from Glatt

Cellets) Suitable polymeric binders include any of those disclosed herein, such as powdered, modified cellulose (eg, propylcellulose, propylmethylcellulose (hydroxypropylcellulose)) , sodium carboxymethyl cellulose), alginic acid, polyethylene. Pyrrolidone (povidone) and mixtures thereof. The amount of topiramate in the topiramate layer, as well as the thickness of the topiramate layer, can be modified to provide a therapeutically effective amount of topiramate. In one embodiment, the topiramate-containing layer comprises from about 9% to 99% topiramate and from about 1% to about 1% polymer dry. The topiramate-containing particles of the ODT composition described herein (e.g., crystalline granulated trays, or esters, or slabs of beads/pellets) are coated with a taste masking layer. The taste masking layer may comprise a water-insoluble polymer and a water-soluble or gastric-soluble or enteric porogen for the grouping of one or more pore formers to increase the release rate of topiramate through the taste masking layer. . ', porogens are typically readily soluble in water or saliva, while the stomach is soluble into 15342l.doc -16 - 201127375. Oral agents are usually insoluble in water and saliva, but in acidic conditions (eg in human subjects) Those conditions present in the stomach, typically less than about pH 5), are readily soluble. In contrast, enteric porogen-forming polymers only dissolve in the intestinal region t of the gastrointestinal tract (e.g., at pH conditions found in the gut of a human subject, typically above a pH of about 4.5). Non-limiting examples of suitable water-insoluble polymers can include, for example, ethyl cellulose, polyvinyl acetate (PVA), cellulose acetate (ca), cellulose acetate butyrate (CAB), and under the trade name A methacrylate copolymer available under rEUDRAGIT" (eg Eudragh RL, nicknamed "RS, Eudraglt NE30D, etc.". Non-limiting examples of water soluble pore-forming polymers may include, for example, polyethylene glycol, poly Vetosterone, propylcellulose, decylcellulose, hydroxypropylcellulose, and mixtures thereof. Non-limiting examples of gastric soluble porogens can include, for example, calcium carbonate, magnesium citrate, magnesium hydroxide, And mixtures thereof. Non-limiting examples of gastric soluble pore-forming polymers may include, for example, Eudragit® E1〇〇/Ep〇 (aminoalkyl methacrylate and neutral methacrylate), AEA® (polyethylene B) Acetal diethylaminoethyl ester, available from Sankyo Co., Ltd. (Tokyo), and mixtures thereof. Non-limiting examples of enteric pore-forming polymers may include, for example, cellulose acetate phthalate, hydroxypropyl fluorene fiber Vitamin phthalate, Eudragit® L1〇〇4S100, and mixtures thereof. When a porogen is present in the taste masking layer, the water-insoluble polymer is water soluble, gastric soluble or enteric. The ratio of the blister may vary from about 95/5 by weight to about 5 〇/5 〇 by weight, or any other ratio therein. The amount of the taste masking coating may range from from 5% to about 3G% of the taste masking The total weight of the particles containing the ruthenium (iv), or about 153421.doc 201127375 from about 10% to about 15% to about 20 〇 / 〇 - 5% - 25%, about 5% - 20%, about 5% - 15. / 〇 , about 5%_1〇% 30%, about 10%-25%, about l〇%-2〇%, about 1〇% 15% 30%, about 5〇%-25%, about 15%_20%, about 2〇% 3〇% 25%, or about 25%-3G%, or any other value or range of values within the ranges recited. 'The ODT compositions described herein include rapidly dispersed pellets, The rapidly dispersing granules comprise a disintegrant and a sugar alcohol and/or a saccharide. The rapidly dispersing granules typically comprise a sugar alcohol (such as mannitol) and/or a saccharide (such as lactose) & a super disintegrant (such as crospovidone). Beta alcohol and / The saccharide and the disintegrant are usually present in the rapidly dispersing granules in a ratio of from about 99:1 to about 9 〇:1 〇 (sugar alcohol and/or saccharide: disintegrant). The disintegrant may include one " Super disintegrant." Non-limiting examples of so-called superdisintegrants may include cross-web steel (cross-linked pvp), sodium starch glycolate, cross-linked (tetra)methylcellulose nano, low-substituted (tetra)-based cellulose, and mixtures thereof. The amount of disintegrant in the rapidly dispersing granules may range from about 1% to about 5% or about 5% to the total weight of the rapidly dispersing granules, for example about 1%, about 2%, about 3 %, about 4%, about 5%, about 6%, about 7% 'about 8%, about 9%, or about 1%, including all ranges, sub-ranges, and values therebetween. Sugar alcohols are typically vaporized forms of carbohydrates in which a carbonyl group (e.g., an aldehyde or ketone) has been reduced to a primary or secondary hydroxyl group. Non-limiting examples of suitable sugar alcohols for use in the rapidly dispersing pellets of the DT composition of the present invention may include, for example, arabitol, ISGMALT® (- consisting of two sugars, glucose and mannitol) Two 15342 丨.doc -18- 201127375 sugar), erythritol, glycerol, lactitol, mannitol, sorbitol, maltitol, and mixtures thereof. The term "saccharide" is generally synonymous with the term "sugar" and includes monosaccharides (such as glucose, fructose, lactose, and ribose); and disaccharides (eg, sucrose, lactose, maltose, trehalose, and cellobiose). Non-limiting examples of suitable saccharides for use in the compositions of the present invention include, for example, lactose, sucrose, maltose, and mixtures thereof. In still another embodiment, the rapidly dispersing granules can include at least one disintegration The decomposing agent is combined with a sugar alcohol. In another embodiment, the lyophilic rapidly dispersing granules may comprise at least one disintegrant combination. In still other embodiments, the disintegrating agents are included: At least one disintegrant is combined with a sugar alcohol and a saccharide. The amount of sugar alcohol and/or saccharide in the rapidly dispersing granules may range from about 99% to 9G%, or from about 95% to 9%. The total weight of the rapidly dispersing pellets is, for example, about 90%, about 91%, about 92%, about 93%, about 9 as rhodium, about 95%, about 96%, about 97%, about 98%. Or about 99./., including all ranges and sub-ranges in between In some embodiments, the average particle size of the primary particles of the sugar alcohol and/or saccharide is 3 〇μηι or less, such as about 5 to 30 Å, about 5 to 25 μηη, about 5 to 2〇_, about bow to ^μιη, about 5 to 1〇_, about 1 () to 3G (four), about 1 to 25 (four) about ^ to 20 (four), about 10 to 15 μΓΏ, about 15 to 3 (four), about. Is a range of about 15 to 20 μm, about 20 to 30 μm, about 20 to 25 μm, or about 25 to 3 μmη ' or any other value or value. Before coating with a taste masking layer, Isoprene ester particles (eg, crystalline I53421.doc -19·201127375 or non-fluorene-like D-specific esters, granulated π-pyryl esters, or topiramate-layered beads) typically have an average particle size of about 1-100 μm. In some embodiments about b 50 μηη or about 1-30 μπι, or an average particle size as otherwise disclosed herein. After coating with a taste masking layer, the taste-masking contains a carrier. The ester-like particles generally have an average particle size. Not less than about 5 μμηη. If the average particle size is significantly higher than about 500 μη, one includes such particles. The disintegrated 〇dt may have an unpleasant "gravel-like" texture in the patient's mouth and may require additional measures to increase palatability. When the average particle size is less than about 00 μηη, the decomposed ODT is usually in the patient. The mouth has a more palatable "creamy" texture. The amount of rapidly dispersing granules or the amount of disintegrant-sugar alcohol/sugar combination compared to odor-containing granules containing oxime esters The amount of disintegrant-sugar alcohol/sugar combination in the composition of the present invention may range from about 40% depending on the desired rate of disintegration and desired organoleptic properties including taste masking, mouthfeel and aftertaste. Up to about 95% 'including about 4%, about peach, about 5%, about 55/〇, about 60%, about 65%, about 7〇%, about 75%, about 8%, about jumping, about 90%, and about 95%, including all values, ranges, and subranges therebetween. In one embodiment, the amount of disintegrant-sugar alcohol/sugar combination is from about 60% to 70% of the total weight of the composition. In another embodiment, the amount of disintegrant-sugar alcohol/sugar combination is about 65% by weight. The ODT compositions described herein contain a sufficient amount of taste-masked drug-containing particles to provide a therapeutically effective amount of tolperine. The amount of the pharmaceutical component in the ODT compositions described herein can range from about 5% to about 25% 'including about 5%, about 1%, about 15%, about 2%, and about 153,421.doc 20-201127375 25 % 'includes all values, ranges, and subranges in between. In addition to acceptable disintegration and organoleptic properties. ^ Commercially acceptable ODT formulations typically require a blister/squeezing that fits into the bottle or is packaged into a pile film base and/or release paper base. Hardness and brittleness for storage, transportation and commercial distribution in development. Thus, in addition to the taste-masked topiramate-containing granules, disintegrants, and sugars and sugars, the ODT compositions described herein may also include other hydrazine, other acceptable ingredients or excipients. The ingredients or excipients may aid in the formation of tablets having acceptable hardness and brittleness characteristics, facilitating n-Fengshanchu <resolving and/or improving the ODT preparations Sensory characteristics. Examples of suitable excipients for use in the compositions or dosage forms described herein may include fillers, diluents, glidants, disintegrants, dry (d) emollients, and the like. Other pharmaceutically acceptable excipients may include acidifying agents, alkalizing agents, preservatives, antioxidants, buffers, chelating agents, coloring agents, complexing agents, emulsifying agents, and/or solubilizing agents, flavoring agents, and flavoring agents, Humectants, sweeteners, humectants, etc. Examples of suitable fillers, diluents and/or binders may include lactose (e.g., spray dried lactose, alpha lactose, strontium lactose, TaMet®®, different grades of Pharmatose®, Microtose® or Fast- Floe®), microcrystalline cellulose (eg Avicel PH101, Avicel PH102, Ceolus KG-802, Ceolus KG-1000, pros〇iv SMCC 50 or SMCC90, different grades of Elcema®, Vivacel®, Ming Tai® or Solka-Fl 〇c®), propylcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropylmethylcellulose (HPMC) (eg Methocel E, F and K, Shin-153421.doc -21 · 201127375

Etsu's Metolose SH is like Methocel E and Metolose 60 SH at 4,000 cps, Methocel F and Metolose 65 SH at 4,000 cps, 4,000, 15,000 and l〇〇, Methocel K at the 〇〇〇 level; and 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), mercapto cellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A1 5C, Methocel A4M), ethylcellulose, sodium carboxymethylcellulose, carboxymethylhydroxyl Ethyl cellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrin, maltodextrin, starch or modified starch (including potato starch, corn starch and rice starch), calcium phosphate (for example, alkaline calcium phosphate, calcium hydrogen phosphate, hydrogen phosphate dihydrate), calcium sulfate, calcium carbonate, sodium alginate, collagen, and the like. Specific examples of the diluent may include calcium carbonate, two-domain phosphoric acid dance, three-domain linonic acid, sulfuric acid, microcrystalline cellulose, powdered cellulose, dextran, dextrin, glucose, fructose, kaolin, lactose. , mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar, and the like. Specific examples of the glidant and the lubricant may include stearic acid, stearic acid town, calcium stearate or other metal stearate, talc, wax and glycerin, light mineral oil, peg, glycerin twenty-two Alkanoic acid ester, colloidal cerium oxide, hydrogenated vegetable oil, corn starch, sodium stearyl fumarate, polyethylene glycol, hospital based sulfate, sodium benzoate, sodium acetate, and the like.

Other excipients may include, for example, flavoring agents, coloring agents, taste masking agents, pH adjusting agents, buffering agents, preservatives, stabilizers, antioxidants, wetting agents, humidity regulators, surfactants, suspending agents, absorption enhancers , release of improvers, and the like. 15342l.doc 22- 201127375 Non-limiting examples of flavoring agents can include, for example, up to about 3% (based on the weight of the tablet), cherry, mint 'orange +, or other acceptable fruit flavorings, and mixture. In addition, the compositions of the present invention may also include up to about 2% by weight (based on the weight of the tablet) of one or more sweeteners such as aspartame, sucralose, or other pharmaceutically acceptable increase. Sweetener or a mixture thereof. Further, the composition of the present invention may be included in a weight of up to 0.5 / 〇 (based on the weight of the tablet), one or more of the coloring agent red # 7 (弼 lake), FD & C red # 27 (aluminum lake) , FD & C Blue # 1 (aluminum lake). The k oxidizing agent may include, for example, ascorbic acid, ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), hypophosphorous acid, monothioglycerol, potassium metabisulfite, gallic acid. Acid propyl ester, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, 'fertility half sucrose vinegar, TPGS or other tocopherol derivatives, and the like. For example, the ODT compositions described herein can include a synthetic sweetener such as sucrose, a flavoring such as cherry flavoring, a tableting aid such as microcrystalline cellulose, and an additional disintegrant. When the ODT compositions described herein include rapidly dispersing microgranules, the composition may also include an additional disintegrant. The additional disintegrant may be the same disintegrant used in the rapidly dispersing microgranules or a different disintegrant. Additional disintegrants may be present in the DT composition of the present invention at up to about 丨〇% (based on the weight of the β hai tablet), for example up to about 1. /〇, up to about 2%, up to about 3%, up to about 4%, up to about 5%, up to about 6%, up to about 7%, up to about 8%, up to about 9. /. Or up to approximately 153421.doc •23·201127375 ίο%, including all ranges and sub-ranges in between. Specific examples of the additional disintegrant may include, for example, sea evaporated acid or alginate, microcrystalline cellulose, propylcellulose, and other cellulose derivatives, crosslinked methyl cellulose sodium, crospovidone , Pollackin clock, Palace powder sodium glycolate, starch, pregelatinized starch, carboxymethyl starch (such as PHmc) ge1% Explota^ and so on. Specific examples of the dry agent may include, for example, gum arabic; full acid, agar, horn gum, slow methylcellulose nanofine cellulose, dextrin, ethyl cellulose, gelatin, liquid glucose guar knee , propylmethylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch, and the like. In another embodiment, the 〇DT compositions described herein may comprise a taste masking layer microencapsulation comprising from about 25/〇 to 55 /〇, including a water-insoluble polymer such as ethyl cellulose. Topiramate crystals; about 8% to 4% by weight of rapidly dispersing pellets (for example, including crospovidone and mannitol); about 5% of additional degumming agents (eg, crospovidone); 1% of one or more flavoring agents, and about 0.5% to 1% of a sweetener (eg, tri-sucrose). The DT composition described herein can comprise a therapeutically effective amount of topiramate coated with a taste masking layer, for example in the form of a tablet, the tablet further comprising rapidly dispersing granules, such rapidly dispersing granules It includes a disintegration W and a sugar alcohol and/or sugar. When administered, the rapidly dispersing pellets of the DT tablet of the present invention rapidly swell and/or dissolve in the oral cavity of the patient' thereby causing the ODT tablet to disintegrate into a taste-masked containment. The particles of the ester form a smooth, palatable, swallowable suspension. In another embodiment, the 〇DT compositions described herein may include topiramate-containing microparticles, one or more flavoring agents, a sweetener, rapidly dispersing microgranules, 153421.doc •24-201127375 flavor, Microcrystalline cellulose, an additional disintegrant, and a lubricant such as magnesium stearate are pressed into an orally disintegrating tablet. The orally disintegrating tablet thus formed rapidly disintegrates when contacted with saliva in the oral cavity, and has a pleasant taste, a "creamy" mouthfeel, and typically provides a rapid, substantially complete in the stomach. The topiramate dose was released without causing significant gastric irritation. In yet another embodiment, the 〇DT compositions described herein can include taste-masked drug microparticles, and optionally flavoring agents, sweeteners, and a device for pre-lubricating the mold and the punch. Other pharmaceutically acceptable excipients in the tablet press of the external lubrication system thereby providing an additional lubricant-free ODT formulation. The orally disintegrating tablets thus produced typically exhibit insufficient hardness and sufficiently low brittleness to be suitable for encapsulation into high density polyethylene (HDPE) bottles and extruded film based or release paper bases using conventional equipment. The blister pack or alu_aiu pouch is used for storage, transportation and commercial distribution. The optional flavoring agents, sweeteners, and other pharmaceutically acceptable excipients, tablet presses, and the like, as well as compression conditions, include, for example, in U.S. Patent Application No. US 2009/0202630, US 2009/0155360, US Those described in 2009/0169620, US 2009/0092672, US 2007/0196491, US 2007/0190145, US 2006/0105039, US 2006/0105038, US 2006/0078614, US 2006/0057199, and US 20050232988, for all Purpose Each of these is incorporated herein by reference in its entirety. The rate of disintegration of the ODT compositions described herein in the oral cavity of a patient may be 153421.doc -25 - 201127375 being the following grade, ie about 60 seconds or less, about 50 seconds or less, about 40 seconds or less, About 30 seconds or less, about 20 seconds or less, or about 1 second or less (including all ranges and subranges therebetween). The rate of disintegration can also be measured using different in vitro testing methods such as the USP <701> disintegration test. The disintegration rate of the ODT compositions of the invention described herein when using the USP <701> disintegration test. The rate of disintegration is generally faster than conventional, non-ODT immediate release topiramate-containing compositions, such as 60 seconds or less, 30 seconds or less, 20 seconds or less, or 1 second or 5 seconds or less. . The term "non-〇dt immediate release of a composition containing topiramate" means a conventional tablet or capsule intended to be swallowed and absorbed in the gastrointestinal tract, or a η and mouth piece which requires 0 and chews to break the structure of the tablet, and they are There is no extended release coating or controlled release coating for delaying the release of topiramate. The dissolution rate of the ODT described herein can be performed using the United States Pharmacopoeia device 2 (paddle @50 rpm in 900 mL of 0.01 or 0.1 N HCl, pH 3.0 or 4.5 or 6.8 (phosphate) buffer or pure water). Evaluation. When the U.S. Pharmacopoeia device 2 is used, the dissolution rate of the drug (e.g., the terpene ester) is comparable to the dissolution rate of a conventional, non-ODT immediate release topiramate-containing composition, e.g., about 70% released within 30 minutes. , about 75%, about 8%, about 85%, about 90%, about 95%, or about 1% of topiramate. In other words, for the test formulation and reference in the relevant dissolution medium. The comparative dissolution rates of such formulations are similar. The 〇dt compositions of the present invention described herein when placed in the mouth until whimper provide good taste masking (eg, when at about 11 约 7 在Simulated saliva 153421.doc -26- 201127375 Releases no more than about ι〇% of the (four) dose in about 3 minutes when the dissolution test is performed. When evaluating using the USP <70b disintegration test, as described here The -ODT will typically disintegrate in about 30 seconds and will typically disintegrate in about 6 seconds when contacted by saliva in the body cavity to form a taste-masking microfeel with an acceptable aftertaste. a smooth, easy-to-swallow suspension of particles that is taste-masked when entering the stomach The microparticles will typically provide for a substantially complete release of the topiramate dose in the DT (eg, when released at a wedge: gastric juice or GG! N HC1 for a dissolution rate of no less than about 50 in minutes) % or not less than about 60% of the topiramate dose.) According to an embodiment of the present invention, particles containing a musical substance (for example, topiramate-containing particles) can be prepared by any suitable method. For example, by using a crystal of a musical substance, One or more disintegrants and one or more fillers (eg, glycolic, sugar, and/or microcrystalline cellulose) are used in a high shear granulator or a 1 bed & granule machine - or a plurality of polymers The mixture-solution is granulated to prepare the drug-containing granules of the present invention, and is dried on a tray in a fluidized bed apparatus in a hanging drying phase to produce, for example, pellets containing enthalpy. ' can be, for example, dissolved or dissolved in a pharmaceutically acceptable solvent (eg, water, alcohols such as B:, propyl), sulphur such as cyclohexanthate, and Their combination) t of the drug and the mixture of 4 compounds A solution is layered onto an inert: S (eg, bead beads, cellulose beads, or Shishi stone beads) to prepare a drug-containing granule. J ^ In certain embodiments of the invention, the solvent may be used Coacervation or micro 153421.doc -27- 201127375 Encapsulation technology by phase in combination with a water-insoluble polymer, or a combination of a water-insoluble polymer and a gastric-soluble porogen (such as calcium carbonate) The topiramate-containing granules (eg, topiramate-containing granules) are coated with a taste masking layer by the method described in U.S. Patent Application Serial No. 11/213,266, the entire disclosure of which is incorporated herein by reference in its entirety for all purposes. Material, ton of vinegar body and / or care. Coating is carried out than the beads layered with the ester). For example, in one embodiment, topiramate can be layered onto the sugar spheres in a fluidized bed granulator and a protective seal coat (e.g., 〇padry CIear) can be provided. Then, as described in U.S. Patent Application Serial No. 11/256,653, the entire disclosure of which is incorporated herein by reference in its entirety, in the in the in the The porogen (e.g., calcium carbonate) phase is combined in cyclohexane for microencapsulation (e.g., by phase separation) to form the topiramate-layered beads to taste-mask the beads to provide taste-masking beads. Alternatively, it may be used according to the present invention by a fluidized bed coating method or a solvent agglomeration method - the taste masking layer will have an average particle size range of about 00 μηι, about 5 〇 _15 〇 μηη, or any of them. The value or range of values for topiramate (and/or one or more other drugs) crystals are coated. The crystalline topiramate having an average particle size of about 5 μηι to 50 μηι can also be taste masked by solvent coacervation as described herein. In certain other embodiments of the invention, an enteric polymer or a combination of a water-insoluble polymer and an enteric polymer may be used by a blanketing method to mask the taste layer. Topiramate-containing granules (e.g., granules containing tortoise, granules, granules, and/or susceptibility beads) are coated. The enteric polymer may be selected from the group consisting of: hydroxypropylmethylcellulose or styrene fiber bismuth bismuth (tetra), acetic acid arbitrarily 253421.doc -28- 201127375

A-long, minus, quasi-I acetate vinyl phthalate, a PH-sensitive methyl methacrylate copolymer commercially available as Eudragit L or S polymer, or a combination thereof. Alcohol and/or drug abuse and dependence are widespread and it is estimated that between 2000 and 20 million American adults in 2000 abused or relied on alcohol and/or drugs. Neurophysiological studies of alcohol dependence and drug dependence suggest that alcohol- and drug dependence and abuse may be associated with alcohol or drug-mediated stimulation of the reward pathway within the Great Moon®, which is linked to alcohol and/or other The increase in dopamine levels associated with drug intake is caused. J〇hns〇n and colleagues (Johnson, A. et al. (2003). "Oral t〇Piramate for treatment of alcohol dependence: a randomized controlled trial'·· The Lancet 361: 1677-1685; Johnson , BA;

Rosenthal, N.; Capece, JA; Wiegand, F.; Mao, L.; Beyers, K.; McKay, A.; Ait-daoud, N. et al. (Oct 2007). "Topiramate for treating alcohol dependence : a randomized controlled trial". 298 (14): 1641-1651) Assume that topiramate can effectively treat alcohol dependence by several mechanisms, including the ability to reduce the extracellular release of dopamine in the midbrain and antagonize at the neuroreceptors Glutamate activity. Most drug therapy trials on alcoholism and/or drug addiction focus on treatment with a single pharmacological agent. However, studies with opioids (such as naltrexone) have demonstrated that opioids μ (eg, beta endorphin), dopamine, serotonin (5-HT), gamma-aminobutyric acid (GABA), and glutamate. The importance of receptors for the development and maintenance of alcohol dependence. Johnson and colleagues (WO 2009/029308) studied the use of a combination of a variety of drugs such as tolby vinegar, ondansetril, and naltrexone using dry ε 153421.doc •29-201127375 For the treatment of alcoholism and drug addiction. Appetite suppressants such as phentermine have been widely used, either prescription or over-the-counter, for achieving/maintaining weight loss. U.S. Patent Application Publication No. 2009/0054372 discloses the use of topiramate, phentermine, for achieving or maintaining weight loss. And a variety of methods and kits for vitamin B-12. For the treatment of alcoholism, drug addiction, together with achieving/maintaining weight loss, if the dosage form comprising the combination of the required drugs is available as a patient-friendly, convenient, and compliant orally disintegrating tablet, this is the most Hopeful. U.S. Patent Application Publication No. 2009/0054372, the entire disclosure of which is hereby incorporated by reference in its entirety in its entirety in the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire disclosure And a method and a plurality of kits for vitamin B-12 (such as cyanocyanine). ρ 〇 专利 专利 专利 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 A combination of Qufu, and/or Ondans. Thus, the ODT compositions as described herein may also optionally include one or more additional active pharmaceutical knives suitable for treating the conditions described herein and individually masking them. For example, by topping off taste-containing topiramate-containing granules, taste-masked phentermine-containing granules, and optionally taste-masked vitamin B-12 granules, rapidly dispersing granules, and other ODT excipients Mix and compress into an orally disintegrating tablet to prepare a combination 〇 DT product that is 153421.doc -30- 201127375 and/or maintains weight loss. . Can use one insoluble

Uniform dispersion in both ODT. A water-insoluble polymer can be combined with a gastric-soluble polymer such as Eudragit E100 or EP0 (a copolymer of aminoalkyl methacrylate) by, for example, fluidized bed coating, with US patents The method described in Application No. 11/248,596 (which is hereby incorporated by reference in its entirety for all its purposes); Beads) for taste masking. For example, a fluidized bed coater equipped with a bottom spray of a Wurster insert is used to layer a drug (eg, a toluene ester) dissolved or suspended in a polymer binder solution to an inert particle (5 〇 1 〇〇目 or about 5〇_3〇〇μπι diameter) such as sugar spheres or cellulose spheres (eg Celphere® CP-203). The drug-layered beads can then be taste masked by fluidized bed coating or by solvent agglomeration as described herein. In a specific embodiment, a water-insoluble polymer (such as ethyl cellulose), a phase inducer (such as polyethylene), and topiramate are charged in 15342I.doc • 31- 201127375 - containing cyclohexane The coagulation tank. The mixture in the tank was heated to about (iv) to dissolve the ethyl fiber, and then slowly cooled under controlled conditions thereby causing microencapsulation of the particles containing the vinegar with ethyl cellulose. When the ambient temperature is reached, the microencapsulated suspension containing the π-grinding granules is subjected to hydration and washed with fresh cyclamen and dried to reduce (4) the solvent level remaining to be accessible. Within limits (eg 'below about 4,0 〇〇 ppm). In one embodiment, the residual solvent is present at a level of less than about (9) ppm. The microencapsulated topiramate-containing granules may have a coating weight ranging from about 3% to about, including about 5. /. , 10%, 15%, 2%, and grab, including all ranges, sub-ranges, and values between them. Thus, examples of agglomeration processes are disclosed in U.S. Patent Nos. 5,252,337, 5,639,475, 6,139, 865, and </RTI> 495, 156, each of which is incorporated herein by reference in its entirety for all purposes. Alternatively, the coagulating liquid may comprise a mixture of a water insoluble polymer (e.g., ethyl cellulose) and a water insoluble or gastric soluble pore former (e.g., carbonium under calcium). The ratio of water-insoluble polymer to porogen may range from 50/50 to 95/05, including about 55/45, about 60/40, about 65/35, about 70/30, about 75/25, about 80/20, approximately 85/15, and approximately 90/1 〇, including all ranges, sub-ranges, and values in and between them. The coated weight of the encapsulated drug particles can range from about 3% to about 20%, including about 5%, 7.5%, 10%, 12.5%, 15%, and 17.5%, including all ranges in and between , subrange, and value. In one embodiment, the agglomeration step comprises suspending the particles containing the oxime 153421.doc • 32-201127375 decyl ester in a solution of ethylcellulose in a coagulation tank at about 8 〇〇c. During the cooling cycle, a micronized porogen is introduced into the tank at a temperature of about 58 ° C while continuously stirring the suspension to evenly distribute the pore former during the forming/hardening phase. Microcapsules - in the film. An example of such a coacervation process is disclosed in U.S. Patent Application Serial No. 1 1/213,266. In one embodiment, the ODT compositions described herein can be prepared by the following methods: (a) granulating topiramate with, for example, a filler and/or diluent such as a sugar alcohol and/or sugar. (b) coating a pellet containing a toluene ester by a fluidized bed coating method or a coacervation method using a taste masking layer such as a water-insoluble polymer such as ethyl cellulose, (c) Optionally, in a high shear granulator (for example, as described in U.S. Patent Application Serial No. 10/356,641, the entire disclosure of which is incorporated herein by reference in its entirety for the entire entire entire entire entire entire entire entire entire entire entire disclosure μ m includes a disintegrant (such as an interpolymerization dimension) and a fast-dispersing microgranule of a sugar alcohol (such as mannitol), (d) the taste-masked Toby Sa pellets and 5 kel of rapidly dispersed granules Blending, and optionally other pharmaceutically acceptable excipients, and (e) compressing the blend into a DT composition. In yet another embodiment, the ODT compositions described herein can be prepared by: (a) dissolving topiramate and a pharmaceutically acceptable binder in a pharmaceutically acceptable manner. A solution or dispersion in a solvent is coated onto an inert core and the solvent is removed to form a topiramate-B-bead, (by) fluidized bed coating process - including water-insoluble ethyl A taste masking layer in which cellulose is combined with an enteric polymer will support. Coated with ester-layered beads, (C) the taste-masked topiramate-layered beads with fast granules of 153421.doc -33 - 201127375 and optionally other pharmaceutically acceptable fumes The agent is blended, and (d) the blend is pressed into an ODT composition. In yet another embodiment, the ODT compositions described herein can be prepared by a method comprising: (4) placing a tray. A solution or dispersion of vinegar and a pharmaceutically acceptable binder dissolved in a pharmaceutically acceptable solvent is applied to an inert core and the solvent is removed to form a topiramate layered bead, (b Applying topiramate-coated beads by a fluidized bed coating or coacervation method using a taste masking layer (such as ethyl cellulose and a gastric-soluble porogen, calcium carbonate), (c) a collapse The decomposing agent and a sugar alcohol and/or saccharide pellet are coated to form a rapidly disintegrating pellet, (d) the taste-masked Toby S layered bead and the rapidly disintegrating pellet and any Other pharmaceutically acceptable excipients are optionally blended, and (e) the blend is pressed into an ODT composition. The taste-masked topiramate particles can include a coating layer that is optionally disposed beneath or above the taste masking layer, thereby making it difficult to include rapidly dispersing pellets and other pharmaceutically acceptable materials. The taste-masked topiramate was clearly seen in the received excipient ODT tablet matrix. In a specific embodiment, the 〇DT composition described herein can be prepared by the following steps: (a) preparing a granule containing a thiophene ester (for example, a shear granulator or a fluidized bed) The coating machine is bonded to a polymer by a topiramate crystalline material having an average particle size of about 5 to 50 μm and one or more diluents/fillers (such as sugar, mannitol, microcrystalline cellulose, and mixtures thereof). The agent is granulated) or topiramate-layered beads (by dissolving topiramate in a polymer binder solution and spraying the topiramate solution onto a inert ball (eg sugar) in a fluidized bed coater Ball or cellulose ball) and using a 153421.doc -34- 201127375 protective seal coat); (b) alone with ethyl cellulose or with gastric-soluble calcium carbonate by microencapsulation technology (coagulation method) or fluidized bed coating method, or using Ethylcellulose and Eudragit £1〇〇 to mask the granules containing the sputum S by the fluidized bed coating method; (c) in a conventional a granulator using water or an alcohol-water mixture to make one or more sugars The alcohol and/or saccharide (each having an average particle size of not more than about 30 μm) is granulated with a disintegrant such as crospovidone, and the granulation is carried out in a fluidized bed apparatus or a conventional oven. Drying to produce a rapidly dispersing microgranule having an average particle size of not more than about (d); (d) masking the drug microparticles of step (b) with or - a plurality of flavoring agents, a sweetener, microcrystalline cellulose, An additional disintegrant and (iv) (e) the rapidly dispersing microgranules are blended; and (4) the blend of step (4) is pressed into an ODT composition. This compression can be accomplished using, for example, a conventional - external lubrication #, system (4)_chip machine for pre-lubricating the molds and punches. Examples of such a method of pre-sliding the mold and punch surfaces are disclosed in U.S. Patent Nos. 5,996,9G2, M25 525, and 6 Winds. All of the objects are referred to by their respective contents. Combine here. The rapidly dispersible granules described herein can be prepared by any suitable method for granulating _ or various disintegrants and/or various sugar alcohols and/or saccharides in a high shear granulator. The rapidly dispersing pellets are prepared and dried in a fluid bed apparatus or on a gas tray in a conventional supply tank to produce the rapidly dispersed pellets. It is also possible to produce rapidly dispersing microgranules by the method described in U.S. Patent Application Serial No. 1()/827'(R)6, the entire disclosure of which is hereby incorporated by reference in its entirety for all purposes: J53421. Doc • 35· 201127375 In a specific embodiment, the ODT compositions described herein can be prepared by the following: 'a blending: (a) by U.S. Patent Application Serial No. 1/827,106; 11/213,266; Topiramate-containing granules (for example, granules containing tortoises), which are masked by any of the methods described in each of the methods described in each of which is incorporated herein by reference in its entirety. (a) a rapidly dispersible microparticle prepared by the method described in U.S. Patent Application Serial No. 1/827,106; and (c) a bead of a layer of ester crystals and/or a mixture of esters; Topiramate-containing granules, rapidly dispersing granules, and other pharmaceutically acceptable ingredients (eg, a flavoring agent-a sweetener, a coloring agent, an additional disintegrant, and/or a compression aid) Blending as microcrystalline cellulose; and (d) pressing the mixture 〇dt composition. This compression step can be accomplished using a rotary tablet press equipped with an external lubrication system for lubricating the mold and the surface of the punch prior to compression. [Embodiment] EXAMPLES The embodiments of the present invention are described in more detail in the following sections with reference to examples. Use includes support. The invention is illustrated by the following examples of brewing. It is to be understood that the examples and embodiments described herein are for illustrative purposes only, and that various changes or modifications thereof are intended to be apparent to those of ordinary skill in the art and should be included And within the spirit and scope of the appended claims. Example 1 1. Pantopiate microcapsules (coating: 2% by weight) 0 kg of hexane, 8 〇〇 吼 吼 vinegar maleate, 2 〇〇 乙基 ethyl fiber 153421.doc -36 - 201127375 Compilation from Dow Chemicals _

Premium; age 100) and 100 g poly _P〇lene C_10 Wax) loaded - equipped with a propeller-type stirrer for 5 plus life. The can was heated to about (iv) while the contents of the can were stirred at 15 G RPMT. Once in the field

The degree reached 79 ° C _ 8 ° ° C, allowing the tank to undergo a controlled rate of cooling. When Z to &lt; sold, the formed microcapsules were passed through and rinsed with fresh cyclohexene and allowed to dry overnight in the hood. The same procedure was followed but a tray having 1% machine % and 15% by weight ethylcellulose coating was also produced by using different amounts of TorrO as the vinegar maleate, ethylcellulose and polyethylene. Specific ester microcapsules. 1.B Rapidly Dispersed Microgranules (95/5 Mannitol/Crossomer) In the presence of pure water as a granulating fluid in a high shear granulator, d_mannitol (152 kg) (with average A sugar alcohol having a particle size of about 15 (four) and a crospovidone XL-1 0 (8 kg) (-disintegrant) are mixed at a ratio of about 9 W and dried in a fluidized bed drier to produce a rapidly dispersing granule Z. (PE278). Alternatively, the wet pellets can be dried by unrolling on a tray in a heated convection tank (PE375). Microcapsules of vinegar pellets at 1X tray (loading amount: 85.0%). The propyl cellulose (Klucel LF, 6 〇〇 g) was slowly added to the monoethanol (190 prf)-water mixture until dissolved. Topirab (1020.0 g) and aqueous lactose (12 〇g) having an average particle size &lt; 2〇^m were charged into a GUu GpcG ^ fluidized bed coater (the fluidized bed coater was equipped - top) Spray % insert "C" air distribution plate; 100 mesh product storage screen) and granulate by spraying the binder solution. Increasing the flow rate (eg 8_25 mL/min): k 153421.doc -37- 201127375 Increase the feed while maintaining the product temperature (eg 40 ° C) and the air volume (eg 40-55 CFM). After the spraying is completed, the resulting pellets are dried in the Glatt apparatus to drive off residual moisture/solvent. Topiramate pellets were taste masked with ethylcellulose (EC-100) (for 15 wt.% coating) according to the procedure of Example 1.A above. 1.0 Torr&quot; than esters 001', 10〇11^ and 20〇11^ will be from the masking of the above example 1.A. Specific ester pellets (120 mg, equivalent to 100-mg of tropidin ester per 100 mg tablet), fast-dispersing pellets (2 13 mg) prepared as described in Example 1 B, and a pre-preparation Mixture (including crospovidone (XL-10: about 20 mg), microcrystalline cellulose (Avicel PH101 from FMC Biopolymers; 40 mg), sucralose (about i 4 mg), FD&C Red #7 (about 1.6 mg) and mint flavor (about 4 mg) were blended for 3 minutes and pressed to ODT using an externally lubricated 13 mm round flat radius _ edge punch. Similarly, an ODT tablet (having an equivalent of 1 〇〇 mg equivalent to twice the weight of the ester tablet) of 200 mg (i.e., equivalent to 2 〇〇 mg Torr.) was prepared. The tablets showed a disintegration time specification of less than 3 sec (when tested by the USP Disintegration Time Test &lt;70 丨&gt;) and released about 8% in 30 minutes. Topiramate therein (when the dissolution test was performed in 9 〇〇 mL of 0.1 N HCl at a blade speed of 5 〇 RPM). Example 2 2.A tray "Zhu grain layered with ester (loading capacity: 45 〇 / 〇)) 6 -8 -8 sugar balls (2331 g) were placed in a Glatt GPCG 5 fluidized bed coater 'The fluidized bed coating machine is equipped with a 1"Wu-insert 153421.doc -38- 201127375, 16 mm pipe, 1 inch column gap, D air distribution plate, 200 mesh production, such as the shell, 4i, size i 〇mm, nozzle cap: rinse. The vinegar (2250 g) was slowly added to the water-organic solvent mixture until it dissolved and the performance was continued for 30 minutes. Hydroxypropyl cellulose (Klucei^, i69 g) was then slowly added to the same solution until dissolved. The sugar spheres were coated by spraying under the following conditions: atomization gas pressure · 2.5 bar; air inlet temperature: 6 〇 ° C; product temperature: about 45 QC gas flow: 6 〇 cfm; flow rate: 8 mL / Min. When the Fuyuancheng drug layered, a 5 wt% protective seal coat (using Klucel LF) was applied to the topiramate layered beads. 2. B. Taste-to-paste ratio g beads The topiramate layered beads, ethyl cellulose, and polyethylene prepared as described in Example 2.A above were charged to a coagulation tank. The topiramate layered beads were microencapsulated under the coating of 6.25% ethylcellulose according to the procedure previously described. The polyethylene content of the tank was varied from 〇 5% to 2% in order to induce the effect of the phase inducer. 2.C Topiramate which is taste-masked with EC-10/EudragitEPO, as disclosed in the copending U.S. Patent Application Serial No. 248,596, issued to U.S. Patent Application Serial No. The polymer was further coated to a weight increase in the ratio of EC-10/EPO/TEC (triethyl citrate) / talc at 40/45/5/10 from the microencapsulated beads from Example 2.B above. About 15% by weight and dried in the same fluid bed coater to drive off residual solvent. According to the same procedure, the 5 wt.% seal from the above example 2.A was sealed by fluid bed coating with EC-10/EPO/TEC/magnesium stearate at a ratio of 42.5/42.5/5/10. 153421.doc • 39· 201127375 The coated tray D is taste-masked to 20% weight increase from the purpose of the beads.

2. The Topiramate ODT of the D-masked beads will be from Example 2.C above at 6.25% EC-100 followed by 15°/. Taste-masked topiramate beads under coating of EC-10/EPO, rapidly dispersible microgranules prepared as disclosed in Example 1.B above, crospovidone (about 5%), microcrystalline cellulose (7) %-10./〇 weight), three-gas sucrose (〇·35 wt.%), mint flavoring (0.7%), and FD&amp;C Red #27 (0.2%), and FD&amp;C Blue# 1 (0.1 5% by weight) was blended in a V-blender for 15 minutes and pressed into 〇DT (25, 50, 100, and 200 mg topiramate equivalents) as described in Example 1.D above. Following the same procedure, the 20% EC-10/EPO coated topiramate beads from Example 2.c above were pressed to 〇dt (with 25, 50, 100, and 200 Claws ratio ester equivalents) Dose strength). Example 3 3. A taste-masked topiramate pellet manufactured in Granurex. Povidone (PVP K-30) was slowly added to pure water while continuously mixing to prepare a polymer mixture solution (10%). The w/w solids will be micronized with a mixture of vinegar and colloidal hydrazine (based on the weight of topiramate 〇 5%) (a glidant), Cab-0-Sil Μ _5 Ρ (from Cab〇t) and povidone in one Blend in a ν-shaped mixer and load into a product of Granurex GX-40 from Vect〇r (Iowa, USA). Spray 10% PVP binder solution at a controlled rate In the rotating bed, the parameters optimized during the formation of the pellet include - process air temperature · about 19 〇 c 2 〇, seat temperature: 16 ° C ± 2. (:; rotor speed: 425 RPM; external air supply : 15 〇 L / min; spray rate: 15 RpM (about 8 mL / min); across the gap 153421.doc • 40- 201127375 pressure = drop: u · 11 mm water column; and during dry pellets - process air volume : 30 CFM; process air temperature: about 6 〇 t; product temperature: pit (to stop drying wide rotor speed: 18 〇 RPM; slit air volume: i 〇 CFM; 4〇min. The pellets thus prepared have about 65% of the particles in the size range of 50-100 mesh. 3 · The toluene ester which is deodorized by phase separation in a 5 gallon coagulation tank will follow the above The topiramate pellets, ethylcellulose, and Ερ〇ι(3)e prepared by the procedure of Example 3A having a drug loading of 85 wt.% and a 5% seal coat (with padry 8 White II) were suspended in cyclohexane. And microcapsules were produced under a 15 wt% coating as previously disclosed. Using a procedure similar to that of Example i A, the topiramate pellets from Example 3.A above were suspended in ethylcellulose and Eplon. Microcapsules with a coating of 13 wt.% were also prepared in (Epolene). Microcapsules with a coating of 17 wt% were also prepared using a procedure similar to that of Example 1-1 A. 3. C. Taste with EC-10/EPO Topiramate according to the procedure described in Example 2.C above, using ethylcellulose (EC-10) and Eudragit EPO in Glatt GPCG 5 at EC-10/EPO/TEC/magnesium stearate at 42.5/42.5/ A ratio of 5/10 (for 25 wt.% of the coating) will be prepared according to the procedure of Example 3.A above with a drug loading of 85 wt.% and a density of 5%. The coating (coated with Opadry® Pink) was coated with an ester IR pellet ().

3.D-masked Granurex pellets&quot; than ester ODTs as described in Example 2.D above, the desired amount of taste-masked topiramate pellets (one part), rapidly dispersed microparticles ( Two parts), crospovidone (5. / 〇 weight 153421.doc • 41 - 201127375 amount), microcrystalline cellulose (1 〇wt_%), mint flavoring (0.66% by weight), and sucralose (0.35% by weight) was blended and pressed into 〇DT (25-mg,

5 0-mg, i〇〇_mg, and 2〇〇_mg). By varying the compression force from approximately 5 kN to 16 kN, it will be equipped with a vacuum delivery system, applicable tools (round, plane radius edge), tablet dust collector, a metal detector, and an external lubrication Matsui A Hata production tablet press of the ExLube system is conditioned to provide a plurality of tablets having a brittleness of less than 5% and a sufficient hardness value. Magnesium stearate is used as a processing aid to externally lubricate the surfaces of the punches and dies, and thus magnesium stearate can be present on the tablets in trace amounts. The weight range for each strength is typically about +5% of the weight of the corresponding target tablet. When the tablet press is running, the ExLube system is activated to ensure that the lubricant is properly sprayed. On the tablet press, the ingot parameters such as the filling depth (匪), the pre-compression position (mm or kN), and the main compression position (mm or kN) are adjusted to produce a piece of each strength that meets the set specifications, according to the With successful setup, the tablet press runs in "automatic mode" until it is completed. During the run, the tablets are periodically sampled to ensure they meet the appropriate processing specifications. Example 4 4.A phentermine microcapsules The ethylcellulose phentermine particles in cyclohexane were microencapsulated to a weight increase of 1 按照 according to the procedure disclosed in Example KA above.

Wt.%, 15% lost, and 2% lost. The dried microcapsules are divided by a suitable sieve to discard oversized particles. 153421.doc •42- 201127375 4.B Vitamin B-12 pellets As disclosed in Example 1.C, a vitamin in propylcellulose ((4% Khice LF) solution is sprayed in Glatt GpcG 3 B_12 (3〇wt%), mannitol (6G Wt.%), crospovidone (5%) and optionally mint flavoring (1%) for granulation. 4.C naltrexone tastes as above As disclosed in Example 4.B, in a Glatt 3 solution, a solution of Klucel LF (5 Λ propylcellulose) was sprayed with naltrex hydrochloride (15 % by weight) and mannitol (78.4%). Granulation with crospovidone and optionally sucralose (〇6%) and cherry flavoring (1%) 4.D Ondansetron taste masking according to the procedure disclosed in Example 1. Ethylcellulose in Hexane The ondansetron hydrochloride particles were microencapsulated to a weight gain of 1% by weight. The dried microcapsules were sieved to discard oversized particles.

4.E topiramate / phentermine hydrochloride / vitamin b-12 〇 DT will be based on the required amount of taste masking π π ratio, taste-masked butyl amine microcapsules, vitamin B-12 (cyanide Cobalamin) pellets, rapidly dispersing microgranules (at least 2 parts relative to a taste-masked (toluene ester + phentermine + B-12)), microcrystalline cellulose (10% Avicel PH101), Crospovidone (5%), tris-sucrose (0.5%), and Loutao § Zhouwei (〇·8 %) • blended together to achieve uniformity and compression into ODT, including 15 mg托" is more than vinegar, 15 mg of phentermine hydrochloride, and 1 mg of vitamin B-12 or 30 mg of topiramate, 30 mg of phentermine, and 1 mg of vitamin B-12. The tablets thus produced were found to rapidly disintegrate in the cavity of 153421.doc -43·201127375 to form a smooth, easy-to-swallow suspension, and the drug that is rapidly released when ingested is bioequivalent/biosimilar to Τ〇Ρ〇 ΜΑΧ (25 or 50 mg topiramate) and / or 37.5 mg phentermine.

4.F topiramate/ondansetron/naltrexone hydrochloride DT The desired amount of taste-masked topiramate, taste-masked ondansetron beads, taste-masked naltrexone pellets, rapidly dispersing microgranules (relative to a taste-masking (t. vinegar + ondansetron + naltrexone) 2 parts), microcrystalline cellulose (丨〇% Avicel PH101), crospovidone (5%), three gas Sucrose (〇.5%), and cherry flavoring (0·7°/〇) were blended until the blend was homogeneous and pressed into 〇dt, which included 25 mg of topiramate, 4 mg of Ondan Siqiong, and 1 mg naltrexone or 50 mg topiramate, 4 mg ondansetron, and 0.5 mg naltrexone. The tablets thus produced are found to rapidly disintegrate in the oral cavity to form a smooth, easy-to-swallow suspension, and the drug that is rapidly released upon ingestion is bioequivalent/biosimilar to T〇P〇MAX (25 or 50 mg topiramate). And / or Acacia (4 mg ondansetron). The present invention has been described in connection with certain embodiments described herein. It is to be understood that the scope of the application and the accompanying claims are intended to Such variations and uses of the various embodiments of the present invention are within the scope of the present invention, and the scope of the present disclosure, as well as the scope of the present disclosure. Change, equivalent or adaptation. 153421.doc • 44 -

Claims (1)

201127375 VII. Scope of Patent Application··1· A taste-masking drug group VIII, Q substance' The composition includes a therapeutically effective amount of taste-masking amino acid SU, you & suiyi-substituted monosaccharide granules, such The granules comprise a #土"-receiving monosaccharide or a pharmaceutically acceptable salt thereof or a derivative of the granules coated with - or a plurality of taste-masking layers for masking/amino-A salt substitution The taste of the monosaccharide; wherein the one or more taste masking layers comprise at least one water-insoluble polymer. The disintegrating tablet comprises: (1) a taste-masking pharmaceutical composition as described in claim 1 of the patent application. And (7) rapidly dispersing microgranules, the I. Isophoric microgranules comprising at least one disintegrant and at least one sugar alcohol and/or at least one saccharide. 3. Female patent 1 | The orally disintegrating tablet 'the orally disintegrating tablet is substantially disintegrated in the oral cavity of the patient within about seconds after administration to the sigma cavity of the patient. 4. Oral disintegration as described in claim 2 of the whistle patent scope The film 'when tested by the usp &lt;7〇1&gt; disintegration test, the mouth The disintegrating tablet substantially disintegrates in about % seconds. 5. The taste-masking pharmaceutical composition according to the invention of claim 2, or the orally disintegrating tablet according to claim 2, wherein US Pharmacopoeia Device 2 paddles at a 50 rpm dissolution test in 9 〇〇 mL 〇 j N Hci, about 7 〇 % or more of the sulfamate-substituted monosaccharide or in about 30 minutes A pharmaceutically acceptable salt or derivative thereof is released from the granules. 6 - A taste-masking pharmaceutical composition as described in the scope of the application of the patent application or as claimed in claim 2, claim No. 15342I.doc 201127375 Orally disintegrating tablet, wherein the sulfamate-substituted monosaccharide or a pharmaceutically acceptable salt or derivative thereof is a vinegar or a pharmaceutically acceptable salt or derivative thereof. The taste-masking pharmaceutical composition according to the above aspect of the invention, wherein the sulfamate-substituted monosaccharide or a pharmaceutically acceptable composition thereof The salt or derivative that is accepted is topiramate, and the particles have a U00 0 The average particle size, and the taste-masked topiramate particles have an average particle size of 4 μm or less. 8. The taste-masking pharmaceutical composition as described in the scope of the patent application or as claimed in claim 2 Orally disintegrating tablet, wherein the particles are crystals, microgranules or drug-coated beads, the beads comprising a monosaccharide substituted with the sulfamate or a pharmaceutically acceptable salt thereof or A derivative coated inert core and a polymeric binder. 9. The taste-masking pharmaceutical composition of claim 2 or the orally disintegrating tablet of claim 2, wherein The taste masking layer further comprises a water soluble, gastric soluble, or enteric porogen. 1 〇 药物 掩 掩 掩 掩 掩 掩 掩 掩 掩 掩 掩 掩 掩 掩 掩 掩 掩 药物 药物 药物 药物 药物 药物 药物 药物 药物 药物 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔 口腔Acid-substituted monosaccharide particles. 11. The taste-masking drug composition of the invention of claim 2, or the orally disintegrating tablet of claim 2, wherein the taste-masked sulfamate-substituted monoterpene particles Further included is a protective seal coat comprising a hydrophilic polymer in an amount from about i wt% to about 153421.doc 201127375 wt% of said particles. 12. The taste-masking pharmaceutical composition according to claim 1 of the patent scope or the orally disintegrating tablet according to claim 2, wherein the water-insoluble polymerized oxime is from the group of the group Ethyl cellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral methacryl τ (tetra) copolymer, quaternary amino methacrylic acid s copolymer, and mixtures thereof. 13. The taste-masking pharmaceutical composition of the invention of claim 2, wherein the taste-masking layer further comprises a water-soluble pore-forming agent, The water-soluble pore-forming agent is selected from the group consisting of: povidone, lactose, sodium chloride, sucrose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl fluorenyl cellulose, polyethylene glycol , and mixtures thereof. 14. The taste-masking pharmaceutical composition of claim 1, or the orally disintegrating tablet of claim 2, wherein the taste-masking layer further comprises a gastric-soluble porogen The gastric-soluble porogen is selected from the group consisting of calcium carbonate, magnesium oxide, aminoalkyl methacrylate copolymer, polyethylene acetal diethylaminoethyl ester, and mixtures thereof. The ointment-masking pharmaceutical composition according to claim 1, wherein the taste-masking layer further comprises an enteric pore former. The enteric pore former is selected from the group consisting of cellulose acetate phthalate, hypromellose phthalate, Eudragit® L100 or S100, and mixtures thereof. 16. The taste-masking pharmaceutical composition or orally disintegrating tablet according to claim 9, wherein the water-insoluble taste-masking polymer is soluble or enteric in a water-soluble, stomach 153421.doc 201127375. The porogen is combined to have a ratio of water-insoluble polymeric κ/Valley (raw, lunar, or enteric porogen ranging from about 90/10 to about 50/50. The taste-masking pharmaceutical composition or the orally disintegrating tablet according to claim 2, wherein the water-insoluble polymer is ethyl oryzanol, when it is about 5 (four) The ethylcellulose has a viscosity of about 1 〇 1 〇〇 op when tested. The orally disintegrating tablet of claim 2, wherein the at least one disintegrating agent is at least A sugar alcohol and/or at least one saccharide is present in a ratio of sugar alcohol and/or saccharide to disintegrant of from about 90/1 Torr to about 99 Å. 19. The oral cavity of claim 2 a disintegrating tablet, which causes the disintegration to be selected from the group below, and the composition thereof is: cross-polymerization Orally disintegrating tablets according to claim 2, wherein the sugar alcohol and/or sugar are selected from the group consisting of sodium glycolate, cross-linked slow-methylcellulose, low-substituted (tetra)-based cellulose, and mixtures thereof. a composition comprising: mannitol, xylitol, sorbitol, maltitol, lactose, sucrose, maltose, and a mixture thereof. The taste-masking pharmaceutical composition described in claim 1 or as claimed The orally disintegrating tablet according to the invention of claim 2, further comprising a taste-masking granule comprising a music substance, the granule comprising an amphetamine and/or a phenethylamine appetite suppressant. 22·”Please patent (4) 21 items The taste-masking (four) composition or the oral cavity tablet, further comprising a taste-masking granule comprising vitamin 153421.doc 201127375 B-12. 23. Covering as described in claim 22 A medicinal composition or an orally disintegrating tablet comprising an effective amount of said taste-masking granules, such as tropine ester, acetophenamide, and vitamin oxime 2. 24. The taste-masking pharmaceutical composition or application The orally disintegrating tablet of claim 2, further comprising a taste-masking granule comprising a 5-Ht3 receptor antagonist. 25. The taste-masking pharmaceutical composition or oral cavity rupture according to claim 24 of the patent application. The tablet further comprises a taste-masking microparticle comprising: an opioid receptor antagonist. 26. 27. A taste-masked pharmaceutical composition or oral cavity as claimed in claim 25. The disintegrating tablet comprises - the taste-masking microparticles which are effectively disposed, the microparticles comprising a Toby S, a -5-ht3 f anti-reagent, and an opioid for treating alcoholism or drug addiction A substance receptor antagonist, wherein the 5-HT3 party antagonist is ondansetron or a pharmaceutically acceptable salt thereof and the opioid receptor antagonist is naltrexone. And preparing the granules of the orally disintegrating tablet according to item 2 of the Shenjing patent scope, wherein the granules comprise an amino acid salt-substituted monosaccharide or a pharmaceutically acceptable salt or derivative thereof; </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Mixing the sword and optionally the pharmaceutically acceptable excipient I53421.doc 201127375; and compressing the mixture to form the orally disintegrating 28. The method of claim 27, Standing. These include: ', 丨 preparing the granules A sulfamate-substituted monosaccharide or a pharmaceutically thereof. a salt or a derivative and a binder are dissolved in a pharmaceutically acceptable compound; 彳: accepting a methyl group to form a monosaccharide solution substituted with an amino acid salt; and a solvent to replace the monosaccharide solution substituted with the sulfamate salt The coating is applied to the case and the above pharmaceutically acceptable solvent is evaporated to form the microparticles 29. As described in claim 28, the scope is as described in claim 28. The granule-step includes: , 'In the case of the preparation of the micro-particles: a mono-amino acid-substituted monosaccharide or a pharmaceutically acceptable plurality of polymer-drying agents for granulation to open the filling of f: The microparticles are formed by the agent and only one or both. 30. If you apply for the patent scope, the 27th law. The method of making a package comprising agglomerating wherein the coating comprises fluidization 31. The method of bed coating as described in claim 27 of the patent application. The method of claim 27, wherein the compression system is such that the rotary (four) tablet machine is equipped with an external lubrication system for pre-lubricating the mold and the punch. 33. The orally disintegrating tablet of claim 2, further comprising one or more pharmaceutically acceptable excipients comprising one of I53421.doc 201127375 flavoring agent and/or one increase Sweetener. 34. A method of treating a patient having a partial or primary systemic tonic-clonic seizure, an epileptic seizure associated with Lennox-Gastaut syndrome, and/or dysphagia, the method comprising The patient is administered an effective amount of oral disintegration as described in item 2 of the patent application. 153421.doc 201127375 IV. Designation of representative drawings: (1) The representative representative of the case is: (none) (2) A brief description of the component symbol: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 153421.doc